INVESTIGATE THE MECHANISMS UNDERLYING THE BEHAVIORAL EFFECTS OF STIMULANT DRUGS Effects of Expectation on Brain Responses to Methylphenidate and to its Placebo in Non Drug Abusing Subjects A preliminary summary on the results from the initial 11 subjects recruited for this study was reported last year. In 2005 we completed studies in 5 more subjects and finalized the analysis of the data. The following summarizes the objective, methods and main findings. The response to drugs of abuse reflects the pharmacological effects of the drug and the expectation that the subject has of its effects. This study evaluated how expectation affects the response to the intravenous administration of the stimulant drug methylphenidate and to its placebo in sixteen non-drug abusing controls. The effects of methylphenidate (0.5 mg/kg iv) and its placebo (3 cc saline iv) on brain glucose metabolism (measured by FDG-PET) were evaluated in four conditions: (1) expecting placebo and receiving placebo; (2) expecting placebo and receiving methylphenidate; (3) expecting methylphenidate and receiving methylphenidate; (4) expecting methylphenidate and receiving placebo. Methylphenidate increased whole brain glucose metabolism both when expected (13%) and when unexpected (14%) and the largest increases occurred in cerebellum, thalamus, lateral orbitofrontal cortex (BA 11/477) , dorsolateral prefrontal cortex (BA9/10) and midbrain. Neither the behavioral (signficant increases in high, restlessness, anxiety and drug liking) nor the brain metabolic effects differed between expected and unexpected methylphenidate. In contrast expectation significantly changed the response to placebo; increasing metabolism in right nucleus accumbens, cingulate gyrus (BA 25) and medial BA 11. The effects of expectation on placebo but not on methylphenidate is likely to reflect the strong pharmacological effects of methylphenidate overriding those of expectation. This contrasts with findings in cocaine abusers in whom expectation enhanced methylphenidate?s effects, which highlights the relevance of prior drug experience and conditioning on the sensitivity of drug responses to expectation. Activation of BA 25, nucleus accumbens and medial orbitofrontal cortex (regions involved with emotional reactivity, reward and salience), when subjects expected methylphenidate but received placebo suggests the involvement of these brain regions in processing expectation (anticipation) of a novel stimuli irrespective of it being rewarding or not..Stimulant-Induced Enhanced Sexual Desire as a Potential Contributing Factor in HIV Transmission: The contribution of drugs of abuse to the HIV epidemic has been traditionally associated with the use of contaminated needles by injecting drug abusers. However, increased risk for HIV infection in drug abusers is not just a function of injection drug use since it also occurs in non-injection drug users. Indeed, the facilitation of risky sexual behaviors during drug intoxication is being increasingly recognized as another mechanism by which drugs of abuse contribute to the HIV epidemic. The mechanisms underlying facilitation of risky sexual behaviors during drug intoxication are not properly understood. Here we investigated the effect of the stimulant drug methylphenidate (given intravenously) on sexual desire as a possible contributing factor to risky sexual behavior associated with the contraction of HIV. For this purpose the effects of intravenous methylphenidate (0.5 mg/kg) on self-reports of sexual desire (rated from 0-10) were evaluated in 39 controls and 43 cocaine abusers. Intravenous methylphenidate significantly increased self-reports of sexual desire in controls (1.4 versus 3.7, p < 0.0005) and cocaine abusers (2.7 versus 4.5, p < 0.005). The responses did not differ between the groups. The stimulant-induced enhancement of sexual desire could be one mechanism by which stimulant drugs such as cocaine and methamphetamine increase the risk for HIV transmission even when they are not injected. INVESTIGATE THE NEUROBIOLOGY UNDERLYING VULNERABILITY FOR ALCOHOL ABUSE ? High Dopamine D2 Receptors in Unaffected Members of Alcoholic Families: Possible Protective Factors: Predisposition to alcoholism is likely an interaction between genetic and environmental factors that confer vulnerability and protection. Because alcoholics have low D2 receptors in striatum, while increasing D2 receptors in laboratory animals reduces alcohol consumption, we hypothesized that high D2 receptor levels may protect against alcoholism. The purpose of this study was to test whether high D2 receptors may be protective against alcoholism and whether this protective effect is mediated in part by their modulation of activity in orbitofrontal cortex (region involved in salience attribution) and cingulate gyrus (region involved in emotional reactivity and inhibitory control). For this purpose we compared fifteen non-alcoholic subjects with a positive family history for alcoholism (FP) with sixteen non-alcoholic subjects with a negative family history (FN). Subjects were scanned with positron emission tomography and [11C]raclopride to assess D2 receptor availability and with [18F]fluoro- deoxyglucose to assess brain glucose metabolism (marker of brain function). Personality measures were obtained using the Multidimensional Personality Questionnaire. Dopamine D2 receptor availability was significantly higher in caudate and ventral striatum in FP than FN. In FP, but not in FN, striatal D2 receptors were associated with metabolism in anterior cingulate (BA 24/25) orbitofrontal (BA 11) and prefrontal cortices (BA 9/10) and also with personality scores of positive emotionality. The higher than normal D2 receptor availability in nonalcoholic members of alcoholic families, supports the hypothesis that high D2 receptors may protect against alcoholism. The significant associations between D2 receptors and metabolism in frontal regions involved with emotional reactivity and executive control suggest that high D2 receptors could protect against alcoholism by regulating circuits involved in inhibiting behavioral responses and in controlling emotional responses.